Phenyl, trihalomethyl or heteroaryl sulfoxides having a latent allyl group bound to sulfur as enzyme inhibitors

ABSTRACT

Organic sulfoxides having a latent allyl group bound to the sulfur are enzyme inhibitors of the suicide or Kcat type.

BACKGROUND OF THE INVENTION

This is a continuation-in-part of copending application Ser. No.147,659, filed May 7, 1980 now U.S. Pat. No. 4,388,475 issued 6-14-83,which in turn is a continuation-in-part of copending application Ser.No. 066,603, filed Aug. 15, 1979 (now abandoned).

This invention is concerned with a novel class of enzyme inhibitors ofthe suicide or K_(cat) type in which the latent reactive group is anallylsulfoxide which is in reversible equilibrium with an allylsulfenate: ##STR1##

Suicide enzyme inhibitors are substances bearing a latent reactive groupthat is unmasked by the target enzyme itself, and which after beingunmasked, immediately reacts with the enzyme in an irreversible manner,inactivating it. Enzyme inhibitors of the suicide type are known in theart but until now almost invariably have employed a Michael acceptor asthe reactive species and these are described by Walsh in HorizonsBiochem. Biophys., 3, 36-81 (1977).

The allylsulfoxide-allyl sulfenate equilibrium of reaction scheme A) isalso known in the art and has been studied as an interesting chemicalreaction by Mislow et al., J. Amer. Chem. Soc., 90, 4869 (1968); 92,2100 (1970) and Evans et al., J. Amer. Chem. Soc., 94, 3672 (1972).Generally, allylsulfoxides are unreactive, but allyl sulfenates arehighly reactive electrophiles, and would be expected to capture almostany nucleophile (Nu) in an enzyme that happens to be near it at themoment it is formed: ##STR2##

Usually the nucleophile is one from the protein portion (prostheticgroup) of the enzyme, such as a sulfhydryl, amino, hydroxy, imidazolylor the like. Once the nucleophile is sulfenylated, the enzyme is alteredfrom its native, active form and can no longer function in its intendedrole as a biochemical catalyst.

In the present invention, the latency of the allylsulfoxide group isgenerally secured as a sulfoxide carrying a β-leaving group or as avinylsulfoxide, neither of which is especially reactive. However, in aproperly designed inhibitor, the target enzyme recognizes the group Z asa substrate, and removes a proton. Then (in the case of the β-leavinggroup), the leaving group X departs leaving the allylsulfoxide, or (withthe vinylsulfoxide) the proton is re-deposited with allylicrearrangement, creating the allylsulfoxide: ##STR3## In either case, theallylsulfoxide can now rearrange to the allyl sulfenate which capturesthe enzyme's nucleophile, inactivating it.

The allylsulfoxide-allyl sulfenate rearrangement is facilitated by thenature of the R group attached to the sulfur: the stronger the electronwithdrawing nature of R the better, for example, p-nitrophenyl. Stericacceleration of the rearrangement is also provided by bulkyo-substituents such as o-alkyl and o,o'-dialkyl when R issubstituted-phenyl. Bulky groups such as alkyl and chloro substituted onthe carbon chain adjacent to the sulfur atom also provide stericacceleration. Another type of electronic acceleration of therearrangement is provided by having an electron withdrawing group, suchas cyano, alkoxycarbonyl or the like substituted on the carbon β- to thesulfur atom or, in other words, on the middle carbon of the allyl group.

It is, therefore, an object of this invention to provide a group ofnovel organic sulfoxides wherien one of the substituents on the sulfurcarries such other functional group or groups as to be a latent allylgroup which becomes unmasked upon reaction with a target enzyme andwhich function as enzyme inhibitors of the suicide type.

It is another object of this invention to provide a useful tool ofbiochemical research in the form of selective, very active enzymeinhibitors.

It is a further object of this invention to provide means for inhibitingenzymes, both in vitro and in vivo with the novel organic sulfoxides ofthis invention.

It is a still further object to provide a method of treating diseasestates, the progress of which is dependent on the activity of enzymes,which comprises the administration of an effective amount of an enzymeinhibitor of this invention.

It is also an object of this invention to provide pharmaceuticalformulations comprising one or more of the novel enzyme inhibitors ofthis invention.

DETAILED DESCRIPTION OF THE INVENTION

This invention comprises, as one embodiment, a new class of K_(cat)suicide enzyme inhibitors which are organic sulfoxides of structuralformula: ##STR4## or a pharmaceutically acceptable salt thereof,wherein: R is

(a) phenyl, either unsubstituted or substituted with such as

(1) nitro

(2) cyano,

(3) C₁₋₃ alkylsulfonyl,

(4) C₁₋₃ alkoxycarbonyl,

(5) o-C₁₋₃ alkyl,

(6) o,o-di(C₁₋₃ alkyl),

(7) di(trifluoromethyl), or

(8) fluoro;

(b) trihalomethyl, such as trifluoromethyl or trichloromethyl;

(c) heteroaryl such as

(1) thiazolyl,

(2) imidazolyl,

(3) pyridinyl,

(4) pyrazinyl,

(5) oxazolyl,

(6) pyrimidinyl, or

(7) thienyl; and

R¹ is hydrogen or aminomethyl,

R² and R⁵ are hydrogen;

R³ is a facile leaving group such as

(a) halo such as fluoro, chloro, bromo, or iodo,

(b) C₂₋₄ alkanoyloxy,

(c) toluenesulfonyloxy,

(d) benzenesulfonyloxy,

(e) C₁₋₃ alkanesulfonyloxy,

(f) p-nitrobenzoyloxy, and

(g) hydroxy, or

R² and R³ taken together form a double bond;

R⁴ is hydrogen, or an electron withdrawing group such as fluoro, chloro,--C₁₋₃ alkoxycarbonyl, cyano, trihalomethyl such as trichloromethyl ortrifluoromethyl, or the like;

R⁶ is hydrogen, --COOH, or --CH₂ CH₂ COOH; and

R⁷ is --OH, --NH₂, --SH, --CH₂ OH, ##STR5## or --OPO₃ R⁸ R⁹, wherein

R⁸ and R⁹ are independently hydrogen or C₁₋₃ alkyl.

Pharmaceutically acceptable salts are also contemplated to be within thescope of the present invention and are those prepared from inorganic ororganic acids known in the art to provide pharmaceutically acceptablesalts, such as hydrochloric, sulfuric, hydrobromic, phosphoric,tartaric, fumaric, citric, malic, maleic, ascorbic, acetic, lactic,oleic, pamoic, palmitic, isethionic, pyroglutamic acid, or the like.Also contemplated are the alkali metal salts, such as the sodium andpotassium salts of the acidic enzyme inhibitors. These salts and otherssuch as those resulting from synthetic procedures are readilyinterconvertible from one to another by well-known methods.

The novel enzyme inhibitors of this invention have a high, specificactivity and thus are useful tools for the research biochemist andpharmacologist in studies of biochemical changes in vitro, and in vivo,and in biochemical assays for natural enzyme substrates and the like bystandard enzymological procedures. The enzyme inhibitors are active, invitro, at concentrations as low as about 0.1 mM but are generallyemployed at concentrations of 1 to about 2 mM.

For in vivo studies, the novel enzyme inhibitors of this invention areadministered orally or parenterally, preferably the latter andpreferably intravenously. Dosages of about 0.1 mg/kg to about 50 mg/kgare used depending on the purpose of the experiment, which may requirethe use of the threshold dose or the dose to produce total inhibition ofa particular enzyme.

Many disease states of mammals, including humans, are known to dependfor their progress on the activity or hyperactivity of particularenzymes and treatment of many of these diseases have been devised aroundinhibitors of these enzymes. Accordingly, the novel enzyme inhibitors ofthis invention have utility in the study of certain disease states andin their treatment.

Generally the novel enzyme inhibitors of this invention produce thedesired effect when administered at from 0.1 to about 500 mg/kg bodyweight, preferably at from 1 to about 50 mg/kg of body weight. Thepreferred form of delivery of the instant compounds to domestic animalsis by solution in drinking water or by inclusion in preformulatedfeedstuffs. For human and animal administration, any of the usualpharmaceutical oral forms may be employed such as tablets, elixirs,aqueous suspensions or the like comprising from about 0.1 to about 500mg of the compounds of this invention. Sterile solutions(representatively given for human treatment) for injection comprisingfrom about 0.1 to about 500 mg of the compounds of this invention giventwo to four times daily are also suitable means of delivery.

Representative specific members of the new class of suicide enzymeinhibitors are shown in Table I along with the enzyme to be inhibitedand the pharmacological or medical effect to be elicited. In each case,R represents o- or p-nitrophenyl, o- or p-cyanophenyl, o- orp-methoxycarbonylphenyl, o- or p-methylsulfonylphenyl,o,p-di(trifluoromethyl)phenyl, trifluoromethyl, trichloromethyl,2-pyrimidinyl, 2-pyridyl, 2-imidazolyl, 2-thienyl, 2-thiazolyl,2-oxazolyl, o-methylphenyl, o-ethylphenyl, o-propylphenyl,o,o-di(methyl)phenyl, o,o-di(ethyl)phenyl, or o,o-di(propyl)phenyl.

                                      TABLE I                                     __________________________________________________________________________                        PREPARATIVE           USE,                                                    METHOD                PHARMACOLOGICAL OR                  INHIBITOR           EXAMPLE  ENZYME INHIBITED                                                                           MEDICAL EFFECT                      __________________________________________________________________________     ##STR6##           1, 2     monoamine oxidase                                                                          antidepressant                       ##STR7##                                                                      ##STR8##           3                                                          ##STR9##           1, 2     alanine racemase                                                                           antibacterial                        ##STR10##          3        Sadenosyl methionine decarboxylase                                                         antipsoriasis                        ##STR11##          3        isopentenyl pyro- phosphate                                                                anti-atherosclerosis                 ##STR12##          1, 2     glycollate oxidase                                                                         anti-renal lithiasis                 ##STR13##          3        lactate dehydrogenase                                                                      antipsoriasis                        ##STR14##          1, 2     alcohol dehydrogenase                                                                      anti-alcoholism                      ##STR15##          3                                                          ##STR16##          3                                                          ##STR17##          1, 2     serine transhydroxy- methylase                                                             antipsoriasis                        ##STR18##          1         methionine γ-lyasecystathionine                                        γ-synthetase                                                                         antibacterial                        ##STR19##          3                                                          ##STR20##          1        GABA transaminase                                                                          anticonvulsant                       ##STR21##          3                                                          ##STR22##          1        ornithine decarboxylase                                                                    antipsoriasis  antiarthritic                                                  anticancer                           ##STR23##          3                                                         __________________________________________________________________________

The mechanism by which some of the novel compounds demonstrate theirenzyme inhibiting properties are depicted schematically below.

In the simpler cases in which the functional group, Z, is an amine themechanism is as follows: ##STR24##

The novel process for preparing the novel compounds of this inventioncomprises oxidation of an aromatic thio compound of structure: ##STR25##wherein R, and R¹⁻⁷ are as previously defined with the exception thatany of the substituents R¹⁻⁷ which are sensitive to the conditions ofoxidation of sulfide to sulfoxide carry protective groups.

The oxidizing agent is such as 1-chlorobenzotriazole, H₂ O₂ /V₂ O₅, SO₂Cl₂ /H₂ O/silica gel, Cl₂, Br₂, NaIO₄, acetyl nitrate, Tl(NO₃)₃ or aperacid such as m-chlorperbenzoic acid, preferably the latter. Theoxidation with a peracid is conducted at temperatures from -70° C. toabout 30° C., preferably at about 0°-25° C., in an organic solvent suchas an aromatic solvent, for example benzene, toluene or the like; or achlorinated hydrocarbon such as tetrachloroethylene, chloroform,methylene chloride or the like, for times of a few a minutes to about 4hours.

After the oxidation is substantially complete, any protective groupspresent are removed by standard procedures such as treatment with astrong organic acid such as trifluoroacetic acid to removet-butyloxycarbonyl groups from amines and to cause de-esterification;strong mineral acids to remove trityl groups from amines; and strongbases such as sodium hydroxide or potassium hydroxide to saponifyesters.

EXAMPLE 1 2-Amino-4-chloro-5-(p-nitrophenyl)sulfinylpentanoic acid

Step A: Preparation of N-BOC allylglycine ##STR26##

A mixture of 884 mg of allylglycine, 4.6 ml of water, 4.6 ml of dioxane,1.6 ml of triethylamine and 2.08 g BOC-ON is stirred for 3.75 hours at25° C. Then 15 ml of water and 20 ml of ether are added. The aqueouslayer is separated, washed with ether, acidified to pH 2 with HCl, andfiltered to isolate the crystalline product, 1.4 g, m.p. 109° C.

Step B: Preparation of N-BOC allylglycine benzhydryl ester ##STR27##

N-BOC allylglycine, 269 mg, is treated with 243 mg ofdiphenyldiazomethane in 25 ml of acetonitrile for one hour. The solventis evaporated. Benzene is added, washed with aqueous NaHCO₃ and brine,dried with MgSO₄, filtered and evaporated, affording crystalline productwhich is washed with hexane and dried, 380 mg, m.p. 79° C.

Step C: Preparation of N-BOC2-amino-4-chloro-5-(p-nitrophenyl)thiopentanoic acid benzhydryl ester##STR28##

To 255 mg of N-BOC allylglycine benzhydryl ester in 1 ml of CH₂ Cl₂ isadded dropwise over 45 minutes at -18° C. under N₂, 152 mg ofp-nitrophenylsulfenyl chloride in 1 ml of CH₂ Cl₂. After an hour at 25°C. the solvent is evaporated, leaving a mixture of product I and itsregioisomer II which is partially separated by preparating thin layerchromatography on silica gel with 50:1 (v/v) CHCl₃ :EtOAc. The product,admixed with some II is obtained at Rf 0.4.

Step D: Preparation of N-BOC2-amino-4-chloro-5-(p-nitrophenyl)sulfinylpentanoic acid benzhydrylester ##STR29##

To 128 mg of product from the previous step in 4 ml of CH₂ Cl₂ at 0° C.under N₂ with stirring over 1 hour is added 45.5 mg ofm-chloroperbenzoic acid (MCPBA) (85% pure) in 4 ml of CH₂ Cl₂. After 0.5hour at 25° C. the solution is washed with aqueous NaHCO₃, dried withMgSO₄, filtered and evaporated to afford 131 mg of product admixed withits regioisomer. Complete separation is afforded by preparative thinlayer chromatography on silica gel with 4:1 (v/v) CHCl₃ --EtOAc. Therearmost band, Rf 0.3, provides 40 mg of pure product.

Step E: Preparation of 2-amino-4-chloro-5-(p-nitrophenyl)sulfinylpentanoic acid ##STR30##

The product from Step D, 39 mg, is dissolved in 0.2 ml of anisole andtreated at 0° C. with 1.0 ml trifluoroacetic acid (TFA) for 10 minutes.The excess TFA and then the anisole are pumped off in vacuo. To theresidue are added a few ml each of water and CH₂ Cl₂. The water layer isseparated and evaporated in vacuo, affording 26 mg of pure product asits TFA salt.

EXAMPLE 2 1-Amino-2-chloro-3-(p-nitrophenyl)sulfinylpropane

Step A: Preparation of N-BOC allylamine (2.I) ##STR31##

A mixture of 3.00 ml of allylamine, 30 ml of CH₂ Cl₂, 5.85 ml oftriethylamine an 5.81 ml of BOC-azide is prepared at 0° C. and stirredat 25° C. for 16.5 hours while protected from moisture. It is thentreated with 2 ml of water for 20 minutes, evaporated, treated withethyl acetate, extracted successively with water, aqueous pH 2 phosphatebuffer, water, aqueous K₂ HPO₄ and brine, dried with MgSO₄, filtered andevaporated to afford 5.54 g of product, m.p. 37° C.

Step B: Preparation of N-BOC1-amino-2-chloro-3-(p-nitrophenyl)thiopropane (2.II and 2.III) ##STR32##

To 781 mg of N-BOC allylamine in 7.5 ml of CH₂ Cl₂ at -18° C. is addeddropwise over 2 hours, 1.14 g of p-nitrophenylsulfenyl chloride in 7.5ml of CH₂ Cl₂. The mixture is stirred 1 hour at 25° C. and evaporated,leaving 2.055 g of crystalline product, which is washed with cyclohexaneand recrystallized from 1:1 (v/v) CHCl₃ -cyclohexane. Pure 2.II, 1.089g, is obtained crystalline. The combined mother liquors arechromatographed on 60 g of silica gel with 50:1 (v/v) CHCl₃-ethylacetate, providing a 1:1 mixture of 2.II and 2.III, 651 mg.

Step C: Preparation of N-BOC1-amino-2-chloro-3-(p-nitrophenyl)sulfinylpropane (2.IV) ##STR33##

The product from Step B, 2.II, 207 mg, in 9 ml of CH₂ Cl₂ is treateddropwise at 0° C. over 70 minutes with 121 mg of m-chloroperbenzoic acid(MCPBA) (85%) in 9 ml of CH₂ Cl₂ under N₂. The solution is stirred 1hour at 25° C., washed with aqueous NaHCO₃, dried with MgSO₄, filtered,evaporated (209 mg) and purified by preparative thin layerchromatography on silica gel with 4:1 (v/v) CHCl₃ -ethylacetate,affording 97 mg of pure product, Rf 0.25.

Step D: Preparation of 1-amino-2-chloro-3-(p-nitrophenyl)sulfinylpropanetrifluoroacetate (2.V) ##STR34##

The product from Step C, 78 mg, is dissolved in 0.4 ml of anisole andtreated at 0° C. for 10 minutes with 2.0 ml of trifluoroacetic acid(TFA). The TFA and anisole are pumped off at 20° C., and water and CH₂Cl₂ are added to the residue. The water layer is separated andevaporated, affording 66 mg of pure product.

EXAMPLE 3 1-p-Nitrophenylsulfinyl-3-aminopropene

Step A: Preparation of1-p-nitrophenylthio-3-t-butoxycarbonylaminopropene (3.I) ##STR35##

A solution of 346 mg of 1-p-nitrophenylthio-2-chloro-3-BOC-aminopropane(compound 2.I) (1 mmole) and 124 mg (1 mmole) of DBN* in 25 ml benzeneis refluxed 3 hours, cooled, filtered and evaporated to provide compound3.I.

Step B: Preparation of1-p-nitrophenylsulfinyl-3-t-butoxycarbonylaminopropene (3.II) ##STR36##

Compound 3.I, 310 mg (1 mmole) is stirred in 20 ml of CH₂ Cl₂ at 0° C.,and to it added over 1 hour a solution of 203 mg of MCPBA (85% pure; net172.6 mg, 1 mmole) in 20 ml CH₂ Cl₂. The reaction mixture is aged 30minutes at 25°, washed with aqueous NaHCO₃ and brine, and evaporated toyield comound 3.II.

Step C: Preparation of 1-p-nitrophenylsulfinyl-3-aminopropene (3.III)##STR37##

Compound 3.II, 326 mg (1 mmole), is taken up in 1 ml of anisole and at0° C. treated with 5 ml of TFA for 11 minutes. The TFA and anisole arethen pumped off in vacuo at 30° C. The product 3.III is isolated as theTFA salt by partitioning between water and CH₂ Cl₂ and evaporating theaqueous layer to dryness. The free base is obtained if desired from theTFA salt in water by adjusting the pH to 9, extracting into CH₂ Cl₂ andevaporating the organic solvent.

EXAMPLE 4 1-Amino-2-chloro-3-(trichloromethylsulfinyl)propanetrifluoroacetic acid salt (4.III)

Step A: Preparation of N-BOC1-Amino-2-chloro-3-(trichloromethylthiopropane) (4.I) ##STR38##

To 157 mg N-BOC allylamine in 5 ml CH₂ Cl₂ at -18° is added dropwiseover 5 minutes 186 mg trichloromethylsulfenyl chloroide in 5 ml CH₂ Cl₂.The mixture is stirred 1 hour and evaporated. Pure I is obtained bychromatography on 50 g silica gel, eluting with 50:1 CHCl₃ --EtOAc.

Step B: Preparation of N-BOC1-Amino-2-chloro-3-(trichloromethylsulfinyl)propane (4.II) ##STR39##

To 172 mg of compound 4.I in 6 ml of CH₂ Cl₂ is added dropwise 86 mg ofm-chloroperbenzoic acid (MCPBA) in 6 ml of CH₂ Cl₂. After stirring 1hour, the solution is washed with aqueous NaHCO₃, dried over MgSO₄,filtered, evaporated and purified by HPLC on silica gel eluting withethyl acetate:chloroform (4:1 v/v) to give pure 4.II.

Step C: Preparation of1-Amino-2-chloro-3-(trichloromethylsulfinyl)propane trifluoroacetic acidsalt (4.III) ##STR40##

Compound 4.II, 120 mg, is dissolved in 0.5 ml anisole and treated at 0°for 10 minutes with 2.5 ml trifluoroacetic acid (TFA). The TFA andanisole are pumped off at 30° and 0.1 torr, leaving 4.III as theresidue.

Employing the procedure substantially as described in Example 4, butsubstituting for the trichloromethylsulfenyl chloride used in Step Athereof, an equimolecular amount of the sulfenyl chlorides of structureRSCl wherein R is F₃ C--, ClF₂ C--, and FCl₂ C--, there are producedrespectively: 1-amino-2-chloro-3-(trifluoromethylsulfinyl)propanetrifluoroacetic acid salt;1-amino-2-chloro-3-(chlorodifluoromethylsulfinyl)propane trifluoroaceticacid salt; and 1-amino-2-chloro-3-(dichlorfluoromethylsulfinyl)propanetrifluoroacetic acid salt.

EXAMPLE 5 1-Amino-2-chloro-3-(pyrimidin-2-ylsulfinyl)propanetrifluoroacetic acid salt (5.IV)

Step A: Preparation of 2-chlorosulfenylpyrimidine (5.I) ##STR41##

A solution of chlorine in CCl₄ is prepared by condensing 4.38 mlliquified Cl₂ at dry-ice temperature, and then adding 75 ml CCl₄ at -10°to it. To this solution at 0° is added two small crystals of iodine, andthen 10.0 g 2-mercaptopyrimidine in 35 ml CCl₄ dropwise over 1.5 hours.After stirring another hour, the solvent, excess Cl₂ and HCl areevaporated in vacuo, leaving 5.I as residue.

Step B: Preparation of1-Amino-2-chloro-3-(pyrimidin-2-ylsulfinyl)propane trifluoroacetic acidsalt (5.IV) ##STR42##

Following the procedures substantially as described in Example 4, StepsA, B and C but substituting for the trichloromethylsulfenyl chlorideused therein an equivalent amount of 2-chlorosulfenylpyrimidine, thereis produced the title compound 5.IV.

Employing the procedures substantially as described in Example 5, butstarting with a mercapto compound of formula R--SH, where R is4-cyanophenyl, 4-methyoxycarbonyl, 2,4-di(trifluoromethyl)phenyl orhexafluorophenyl, there is produced the corresponding compound offormula: ##STR43## wherein R is 4-cyanophenyl, 4-methoxyphenyl,2,4-di(trifluoromethyl)phenyl or hexafluorophenyl, respectively.

EXAMPLE 6

Tablets containing 1.0, 2.0, 25.0, 50.0 and 100.0 mg, respectively of2-amino-4-chloro-5-(p-nitrophenylsulfinyl pentanoic acid (activecompound) are prepared as illustrated below:

    ______________________________________                                        Active      Amount - mg/tablet                                                Compound    1.0    2.0    25.0   50.0  100.0                                  ______________________________________                                        Microcrystalline                                                                          49.25  48.75  37.25  100.0 200.0                                  cellulose                                                                     Modified food                                                                             49.25  48.75  37.25  4.25  8.5                                    corn starch                                                                   Magnesium   0.50   0.50   0.50   0.75  1.5                                    stearate                                                                      ______________________________________                                    

All of the active compound cellulose, and a portion of the corn starchare mixed and granulated to a 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and the magnesium stearate. The resulting granulation is thencompressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 50.0 mg, and100.0 mg of active compound per tablet.

Other tablets are prepared using the same procedures and the equivalentamounts of excipients along with equivalent amounts of the other activecompounds of the present invention.

What is claimed is:
 1. The compound of structural formula: ##STR44## ora pharmaceutically acceptable salt thereof, wherein: R is phenyl orphenyl substituted with(1) nitro (2) cyano, (3) C₁₋₃ alkoxycarbonyl, (4)di(trifluoromethyl), or (5) fluoro; R³ is halo; and R⁷ is --NH₂, or##STR45## .
 2. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, whichis:1-amino-3-chloro-3-(4-cyanophenylsulfinyl)propane;1-amino-2-chloro-3-(4-methoxyphenylsulfinyl)propane;1-amino-2-chloro-3[2,4-di(trifluoromethyl)phenylsulfinyl]propane;1-amino-2-chloro-3-hexafluorophenylsulfinylpropane; or2-amino-3-chloro-5-(p-nitrophenylsulfinyl)pentanoic acid.
 3. Thecompound of claim 1 which is 2-amino-4-chloro-5-(p-nitrophenylsulfinylpentanoic acid).
 4. A pharmaceutical enzyme inhibiting compositioncomprising a pharmaceutical carrier and an effective enzyme inhibitingamount of a compound of claim 2 or a pharmaceutically acceptable saltthereof.
 5. A method of inhibiting enzymes in a patient in need of suchtreatment which comprises the administration of an enzyme inhibitoryamount of the compound of claim 1 or a pharmaceutically acceptable saltthereof.
 6. A method of inhibiting enzymes in a patient in need of suchtreatment which comprises the administration of an enzyme inhibitoryamount of a compound of claim 2 or a pharmeutically acceptable saltthereof.